This invention relates to the use of certain tricyclic oxazolones to enhance myocardial contractile force. These compounds are useful as cardiotonics in the treatment of heart failure.
Heart failure is that physiological condition resulting from the inability of the ventricular myocardium to maintain adequate blood flow to the peripheral body tissues and includes congestive heart failure, backward and forward heart failure, right ventricular and left ventricular heart failure, and low-output heart failure. Heart failure can be caused by myocardial ischemia, myocardial infarction, excessive alcohol usage, pulmonary embolism, infection, anemia, arrhythmias, and systemic hypertension. Symptoms include tachycardia, fatigue with exertion, dyspnea, orthopnea, and pulmonary edema.
Treatment involves either removal or correction of the underlying causes or involves control of the heart failure state. Management or control can be accomplished by increasing cardiac output or by decreasing cardiac workload. While workload can be accomplished by reduction of physical activities and physical and emotional rest, increasing cardiac output has traditionally involved digitalis therapy. Digitalis stimulates contractile force of the heart which increases cardiac output and improves ventricular emptying. In this way digitalis therapy normalizes venous pressure and reduces peripheral vasoconstriction, circulatory congestion, and organ hypoperfusion.
Unfortunately, optimal doses of digitalis vary with the patient's age, size, and condition and the therapeutic to toxic ratio is quite narrow. In most patients the lethal dose is only about five to ten times the minimal effective dose with toxic effects becoming apparent at only 1.5 to 2.0 times the effective dose. For these reasons, dose must be carefully tailored to suit the individual and frequent clinical examinations and electrocardiogram is necessary to detect early signs of digitalis intoxioation. Despite this care digitalis intoxication is reported in up to one-fifth of hospitalized patients undergoing therapy.
The need for less toxic and more effective cardiotonic agents is readily apparent. Applicants have discovered certain tricyclic oxazolones which possess potent cardiotonic and vasodilation activity and by comparison to digitalis have few toxic effects.